Microtubule interactions with chemically diverse stabilizing agents: Thermodynamics of binding to the paclitaxel site predicts cytotoxicity

Rubén M. Buey, Isabel Barasoain, Evelyn Jackson, Arndt Meyer, Paraskevi Giannakakou, Ian Paterson, Susan Mooberry, José M. Andreu, J. Fernando Díaz

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

The interactions of microtubules with most compounds described as stabilizing agents have been studied. Several of them (lonafarnib, dicumarol, lutein, and jatrophane polyesters) did not show any stabilizing effect on microtubules. Taccalonolides A and E show paclitaxel-like effects in cells, but they were not able to modulate in vitro tubulin assembly or to bind microtubules, which suggests that other factors are involved in their cellular effects. The binding constants of epothilones, eleutherobin, discodermolide, sarcodictyins, 3,17β-diacetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)- triene, and dictyostatin to the paclitaxel site; the critical concentrations of ligand-induced assembly; and their cytotoxicity in carcinoma cells have been measured, and correlations between these parameters have been determined. The inhibition of cell proliferation correlates better with the binding enthalpy change than with the binding constants, suggesting that large, favorable enthalpic contribution to the binding is desired to design paclitaxel site drugs with higher cytotoxicity.

Original languageEnglish (US)
Pages (from-to)1269-1279
Number of pages11
JournalChemistry and Biology
Volume12
Issue number12
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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